Highly enantioselective hydrogenation of α-aryl-β-substituted acrylic acids catalyzed by Ir-SpinPHOX

Article abstract of DOI:10.1039/b919902k

The enantioselective hydrogenation of a series of challenging substrates, α-aryl-β-substituted acrylic acids, was realized with high efficiency and enantioselectivity (up to 96%) under the catalysis of Ir(i) complex of Spiro-based P,N ligand, SpinPHOX.

Full text of DOI:10.1039/b919902k

View Article Online / Journal Homepage / Table of Contents for this issue
This article was published as part of the
2009 ‘Catalysis in Organic
Synthesis’ web theme issue
Showcasing high quality research in organic chemistry
Please see our website
(http://www.rsc.org/chemcomm/organicwebtheme2009)
to access the other papers in this issue.

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Highly enantioselective hydrogenation of a-aryl-b-substituted acrylic
acids catalyzed by Ir-SpinPHOXwz
Yi Zhang,ab Zhaobin Han,b Fuying Li,a Kuiling Ding*b and Ao Zhang*a
Received (in Cambridge, UK) 24th September 2009, Accepted 11th November 2009
First published as an Advance Article on the web 24th November 2009
DOI: 10.1039/b919902k
The enantioselective hydrogenation of a series of challenging
substrates, a-aryl-b-substituted acrylic acids, was realized
with high efficiency and enantioselectivity (up to 96%) under
the catalysis of Ir(I) complex of Spiro-based P,N ligand,
SpinPHOX.
Enantiopure a-arylpropanic acid and their derivatives are
key intermediates for the synthesis of various biologically
important compounds.1 The development of a straightforward
approach to their direct access represents one of the most
challenging issues in terms of synthetic chemistry, in which
asymmetric hydrogenation of the corresponding prochiral
a-arylacrylic acid derivatives has proven to be the most
promising.2 In the past decades, transition metal catalyzed
Scheme 1 Representative P,N chiral ligands for Ir(I)-catalyzed hydro-
asymmetric hydrogenation of a,b-unsaturated carbonyl
genation of a,b-unsaturated carboxylic acids.
compounds has been very successful.3–5 However, asymmetric
hydrogenation of a-aryl-b-substituted acrylic acids with high
series of biologically interesting carboxylic acids with excellent
yields and up to 96% enantioselectivity.
efficiency remains unsatisfactory. On the other hand, the
asymmetric hydrogenation of unsaturated carboxylic acids
using chiral Ir catalysts has recently received significant
attention. For example, the Ir–PHOX or Ir–SIPHOX complexes
(Scheme 1) have been employed in the asymmetric hydro-
genation of a variety of a,b-unsaturated acids including
2-phenylacrylic acid6 or a-alkyl-b-aryl/alkyl acrylic acids,7
respectively, affording the corresponding optically active acids
in good yields with moderate to excellent ees. Despite of the
facts mentioned above, the catalytic asymmetric hydrogena-
tion of a-aryl-b-substituted acrylic acids 1, the most direct
approach to a key chiral intermediate for the synthesis of
potential antidiabetic drug PSN-GK1 (in phase I clinic),8
still remains a challenging theme (Scheme 1). In the present
communication, we report our preliminary results on the use
of Ir(I) complexes of a novel class of spiro[4,4]-1,6-nonadiene-
based phosphine–oxazoline ligands (SpinPHOX, 2)9 in the
catalytic asymmetric hydrogenation of a variety of a-aryl-b-
substitued acrylic acids (1), leading to the production of a
The trisubstituted a,b-unsaturated carboxylic acid, (E)-2-
phenyl-3-(tetrahydro-2H-pyran-4-yl) acrylic acid (1a), was
initially taken as the model substrate in order to optimize
the hydrogenation reaction conditions. The iridium complexes
of (R,S)-2a and (S,S)-2a were employed as the catalyst
(1 mol%).10 After screening of various reaction conditions
(see Table S1 in electronic supplementary information, ESIz)
including the effects of solvent, temperature, and hydrogen
pressure, the hydrogenation of 1a in methanol at 50 1C under
30 atm of H2 turned out to be optimal. Considering the poor
solubility of the substrate in the reaction medium and the
potential impact of a carboxylate group on the catalysis, we
then examined the effect of base additives on the reaction rate
and enantioselectivity of the catalysis. Notably, the addition of
1 equiv. of NEt37,11 (see Table S2 in ESIz) gave the best result
in terms of both conversion of the substrate and enantiomeric
excess of the product. In the presence of 1 mol% of Ir(I)/(R,S)-2a,
the hydrogenation of 1a proceeded smoothly with 92%
conversion in 20 h, affording (–)-2-phenyl-3-(tetrahydro-2H-
pyran-4-yl) propanoic acid (3a) with 93% ee (Table 1, entry 1).
In order for comparison, Pfaltz’s Ir/PHOX (Ar = Ph, R =
iPr) catalyst was also employed in the hydrogenation of 1a,
31% conv. of substrate and 32% ee of the product were
obtained. It should be noted in the hydrogenation of the
(Z)-isomer of 1a in the presence of (R,S)-2h under identical
reaction conditions, the conversion of substrate is negligible.
The chirality at the spiro backbone of ligand 2 was found to
have a significant impact on the asymmetric induction of the
reaction. The combination of a R configuration in the spiro
backbone and an S configuration in the oxazoline component
a Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences,
555 Zuchongzhi Road, Shanghai 201203, P.R. China.
E-mail: aozhang@mail.shcnc.ac.cn; Fax: (+86) 21 50806035
b State Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai, 200032, P.R. China.
E-mail: kding@mail.sioc.ac.cn; Fax: (+86) 21 64166128
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic chem-
istry. Please see our website (http://www.rsc.org/chemcomm/organic
webtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
details and characterization data for all new compounds. See DOI:
10.1039/b919902k
ꢀc
This journal is The Royal Society of Chemistry 2010
156 | Chem. Commun., 2010, 46, 156–158

Table 1 Substituent effect of ligands (2a–h) on Ir-catalyzed asym-
metric hydrogenation of (E)-2-phenyl-3-(tetrahydro-2H-pyran-4-yl)
acrylic acid (1a)a
Table 2 Synthesis of optically active carboxylic acids (3a–l) with
biological importance via asymmetric hydrogenation of acrylic acid
derivatives 1a–l under the catalysis of Ir(I)/(R,S)-2ha
Entry
R1
R2
Ee (%)b
1
2
3
4
Tetrahydro-2H-pyran-4-yl (1a)
H (1b)
Me (1c)
Ph (1d)
Cyclopentyl (1e)
H
H
H
H
96 (–)
88 (R)
94 (R)
94 (R)
95 (–)
5
H
6
7
8
9
10
11
12
Tetrahydro-2H-pyran-4-yl (1f)
Tetrahydro-2H-pyran-4-yl (1g)
Tetrahydro-2H-pyran-4-yl (1h)
Tetrahydro-2H-pyran-4-yl (1i)
Tetrahydro-2H-pyran-4-yl (1j)
Tetrahydro-2H-pyran-4-yl (1k)
Tetrahydro-2H-pyran-4-yl (1l)
MeO
F
I
MeSO2
c-PrSO2
MeS
c-PrS
95 (–)
95 (–)
Entry
Ligand
Conv. (%)b
Ee (%)c
91c (–)
91 (R)
89 (R)
94d,e (R)
95e (R)
1
2
3
4
5
6
7
8
9
(R,S)-2a
(S,S)-2a
(R,S)-2b
(R,S)-2c
(R,S)-2d
(R,S)-2e
(R,S)-2f
(R,S)-2g
(R,S)-2h
92
93 (–)
69 (+)
84 (–)
58 (–)
92 (–)
92 (–)
94 (–)
83 (–)
96 (–)
> 99
56
59
85
75
> 99
76
> 99
a
For the reaction conditions and analysis of reaction system, see
footnotes a,b in Table 1. The complete conversion of substrates was
b
observed for all entries. Determined on a Chiralcel column after
esterification with diazomethane. The absolute configuration was
determined by comparison of the optical rotation with that reported
a
Reaction conditions: 0.1 mmol scale of 1a with [1a] = 0.1 mol Lꢁ1 in
in the literature.12 c Determined on a Chiralcel AD-H column after
MeOH, PH = 30 atm, s/c = 100, T = 50 1C. Determined by 1H
b
2
d
being transformed to dehalogenated methyl ester. s/c
c
NMR. Determined by HPLC analysis on a Chiralcel AD-H column
= 50.
e
Determined on a Chiralcel OD-H column after being transformed
to their corresponding sulfone derivatives.
after esterification with diazomethane.
was disclosed to be a matched case as in Ir(I)/(R,S)-2a, whereas
the Ir(I) complex of the corresponding diastereomeric ligand
(S,S)-2a gave lower enantioselectivity with opposite asymmetric
induction, although a complete conversion of 1a was observed
in the latter (entry 2 vs. 1 in Table 1). Therefore, the sign of
asymmetric induction in the hydrogenation is predominately
determined by the chirality of the spiro backbone. The exami-
nation of the substituent effect of the oxazoline moiety in
ligand (R,S)-2a–e revealed that (R,S)-2a bearing a phenyl
group was the best in terms of both reactivity and enantio-
selectivity (entry 1 vs. entries 3–6 in Table 1). To further
improve the catalytic performance of the reaction, three new
ligands (R,S)-2f–h bearing different aryl groups at the P atom
were synthesized and employed in the hydrogenation of 1a
(entries 7–9). Gratifyingly, the catalyst composed of ligand
(R,S)-2h with two o-tolyl groups at P-atom showed remark-
able reactivity (>99% conv.) and enhanced enantioselectivity
(96% ee) (Table 1, entry 9).
Table 2, entries 1–8). It is of note that the reaction of b-alkyl
or phenyl substituted acrylic acids (1a, 1c–e) generally affords
excellent enantioselectivity (94–96%) while the parent
a-phenyl acrylic acid (1b) provides a somewhat inferior result
(88% ee), implying that the present catalyst system is parti-
cularly suitable for the sterically more demanding substrate at
the b-position of acrylic acids. On the other hand, the electronic
properties of substituent (R2) at para-position of a-phenyl
ring has less impact on the enantioselectivity of the reaction
(entry 1 vs. entries 6–8, Table 2).
Both the b-tetrahydro-2H-pyran-4-yl moiety and the
sulfonyl unit at the para-position of the a-aryl group of
the carboxylic acid have proven to be critically important in
the chiral antidiabetic drug PSN-GK1 and analogous mole-
cules. Therefore, the development of the catalyst system for
the direct access of these key intermediates is highly desirable.
Accordingly, the ideal catalyst must tolerate the presence of
both sulfonyl and tetrahydro-2H-pyran-4-yl moieties in the
acid substrates or related precursors. As described above, our
catalyst system is particularly effective for the hydrogenation
of substrate 1a containing b-tetrahydro-2H-pyran-4-yl moiety.
The further introduction of an alkylthio- or alkylsulfonyl
group to the para-position of the a-phenyl of acrylic acid 1a
afforded substrates 1i–l, which were subsequently hydro-
genated under the optimized conditions in the presence of
Ir(I)/(R,S)-2h. It was good to find that the hydrogenation
of all these four substrates gave the corresponding carboxylic
acids 3i–l in almost quantitative yields with 89–95% ee
(entries 9–12, Table 2). These facts indicate that the present
catalyst system not only has the advantage of high
With the optimized catalyst Ir(I)/(R,S)-2h in hand, we then
investigated its applicability in the catalysis of trisubstituted
a,b-unsaturated carboxylic acids 1a–l. The substrates were
well-chosen considering the possibility for the use of the
hydrogenation products as the key intermediates for the
synthesis of analogous compounds of PSN-GK1.8 Accordingly,
a variety of a-aryl acrylic acids with various b-substituents
(variation at R1) (1a–e) were prepared and subsequently
hydrogenated in methanol using Ir(I)/(R,S)-2h (1 mol%) as
the catalyst under 30 atm of H2 at 50 1C. The corresponding
hydrogenated carboxylic acids were obtained quantitatively
with good to excellent enantioselectivities (88–96% ee;
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 156–158 | 157

enantioselective control in the reaction but also possesses
excellent substrate functional group tolerance if one considers
the strong coordination tendency of sulfide or sulfone with a
transition metal catalyst. Fortunately, the hydrogenation of 1l
afforded the corresponding carboxylic acid 3l with 95% ee
which can be directly oxidized by mCPBA to give 3j in >99%
yield without any racemization. Simple condensation of 3j
with 5-fluoro-2-aminothiazole gave the antidiabetic drug PSN-
GK1 conveniently in good yield with the same enantiomeric
excess. In order to demonstrate the practicality of the catalysis,
a hydrogenation with 4 mmol (1.2 g) scale of substrate 1l was
carried out in the presence of 1 mol% of (R,S)-2h under
30 atm of H2 at 50 1C, complete conversion of 1l and 95%
ee of 3l were obtained. It should be noted that the chirality of
the stereocenter in the PSN-GK1 molecule is critically impor-
tant for its bioactivity, in which the R-enantiomer has the
desired clinical actions in vivo while the S-enantiomer is
completely inactive, although both R- and S-congeners act
equi-potently in vitro.13 Therefore, the present work has not
only furnished a facile method for rapid synthesis of the
related chiral drug in a large scale for clinical study, but has
also provided an excellent opportunity for generating a small
library of both enantiomers of analogous compounds with the
variation at the a- or b-position of the carboxylic moiety for
further structure–activity-relationship (SAR) study to identify
more potent leading compounds.
Int. Pat., WO 2006/016178, 2006; (b) W. Chen, P. J. McCormack,
K. Mohammed, W. Mbafor, S. M. Roberts and J. Whittall,
Angew. Chem., Int. Ed., 2007, 46, 4141; (c) T. T. Co, S. C. Shim,
C. S. Cho, T. J. Kim, S. O. Kang, W.-S. Han, J. Ko and
C.-K. Kim, Organometallics, 2005, 24, 4824; (d) I. N. Houpis,
L. E. Patterson, C. A. Alt, J. R. Rizzo, T. Y. Zhang and
M. Haurez, Org. Lett., 2005, 7, 1947; (e) R. Hoen, J. A. F.
Boogers, H. Bernsmann, A. J. Minnaard, A. Meetsma,
T. D. Tiemersma-Wegman, A. H. M. de Vries, J. G. de Vries
and B. L. Feringa, Angew. Chem., Int. Ed., 2005, 44, 4209;
(f) T. Hayashi, N. Kawamura and Y. Ito, J. Am. Chem. Soc.,
1987, 109, 7876.
5 For selected examples of Ru catalysis, see: (a) X. Cheng, J.-H. Xie,
S. Li and Q.-L. Zhou, Adv. Synth. Catal., 2006, 348, 1271;
(b) L. Qiu, F. Y. Kwong, J. Wu, W. H. Lam, S. Chan,
W.-Y. Yu, Y.-M. Li, R. Guo, Z. Zhou and A. S. C. Chan,
J. Am. Chem. Soc., 2006, 128, 5955; (c) X. Cheng, Q. Zhang,
J.-H. Xie, L.-X. Wang and Q.-L. Zhou, Angew. Chem., Int. Ed.,
2005, 44, 1118; (d) P. E. Maligres, S. W. Krska and
G. R. Humphrey, Org. Lett., 2004, 6, 3147; (e) C.-C. Pai,
C.-W. Lin, C.-C. Lin, C.-C. Chen and A. S. C. Chan, J. Am.
Chem. Soc., 2000, 122, 11513; (f) Q.-H. Fan, C.-Y. Ren,
C.-H. Yeung, W.-H. Hu and A. S. C. Chan, J. Am. Chem. Soc.,
1999, 121, 7407; (g) T. Uemura, X. Zhang, K. Matsumura,
N. Sayo, H. Kumobayashi, T. Ohta, K. Nozaki and H. Takaya,
J. Org. Chem., 1996, 61, 5510; (h) T. Manimaran, T.-C. Wu,
W. D. Klobucar, C. H. Kolich and G. P. Stahly, Organometallics,
1993, 12, 1467; (i) T. Ohta, H. Takaya, M. Kitamura, K. Nagai
and R. Noyori, J. Org. Chem., 1987, 52, 3174.
6 A. Scrivanti, S. Bovo, A. Ciappa and U. Matteoli, Tetrahedron
Lett., 2006, 47, 9261.
7 S. Li, S.-F. Zhu, C.-M. Zhang, S. Song and Q.-L. Zhou, J. Am.
Chem. Soc., 2008, 130, 8584.
8 (a) L. S. Bertram, D. Black, P. H. Briner, R. Chatfield, A. Cooke,
M. C. T. Fyfe, P. J. Murray, F. Naud, M. Nawano, M. J. Procter,
G. Rakipovski, C. M. Rasamison, C. Reynet, K. L. Schofield,
V. K. Shah, F. Spindler, A. Taylor, R. Turton, G. M. Williams,
P. Wong-Kai-In and K. Yasuda, J. Med. Chem., 2008, 51, 4340;
(b) M. C. T. Fyfe, J. R. White, A. Taylor, R. Chatfield,
E. Wargent, R. L. Printz, T. Sulpice, J. G. McCormack,
M. J. Procter, C. Reynet, P. S. Widdowson and P. Wong-Kai-In,
Diabetologia, 2007, 50, 1277; (c) K. R. Guertin and J. Grimsby,
Curr. Med. Chem., 2006, 13, 1839; (d) R. Sarabu, R. Taub and
J. Grimsby, Drug Discovery Today: Therapeutic Strategies, 2007, 4,
111; (e) M. Coghlan and B. Leighton, Expert Opin. Invest. Drugs,
2008, 17, 145; (f) M. Pal, Drug Discovery Today, 2009, 14, 784;
(g) J. Grimsby, S. J. Berthel and R. Sarabu, Curr. Top. Med.
Chem., 2008, 8, 1524.
This work is partially supported by NSFC (nos. 20632060,
20821002, 20620140429, 30772625), the Chinese Academy of
Sciences, the Major Basic Research Development Program of
China (grant no. 2010CB833300), the Science and Technology
Commission of Shanghai Municipality, and Merck Research
Laboratories.
Notes and references
1 (a) For selected reviews, see: A. L. Ong, A. H. Kamaruddin and
S. Bhatia, Process Biochem., 2005, 40, 3526; (b) C. Ghelardini,
N. Galeotti, M. N. Romanelli, F. Gualtieri and A. Bartolini, CNS
Drug Rev., 2000, 6, 63; (c) J.-P. Rieu, A. Boucherle, H. Cousse and
G. Mouzin, Tetrahedron, 1986, 42, 4095; (d) T. Y. Shen, Angew.
Chem., Int. Ed. Engl., 1972, 11, 460; For selected examples, see;
(e) Y. Lu, T. M.-D. Nguyen, G. Weltrowska, I. Berezowska,
C. Lemieux, N. N. Chung and P. W. Schiller, J. Med. Chem.,
2001, 44, 3048; (f) M. Allegretti, R. Bertini, M. C. Cesta,
C. Bizzarri, R. Di Bitondo, V. Di Cioccio, E. Galliera,
V. Berdini, A. Topai, G. Zampella, V. Russo, N. Di Bello,
G. Nano, L. Nicolini, M. Locati, P. Fantucci, S. Florio and
F. Colotta, J. Med. Chem., 2005, 48, 4312; (g) O. Piccolo,
F. Spreafico and G. Visentin, J. Org. Chem., 1987, 52, 10.
2 (a) J.-P. Genet, in Modern Reduction Methods, ed. P. G. Andersson
and I. J. Munslow, Wiley-VCH, Weinheim, 2008, pp. 18–22;
(b) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley-
Interscience, New York, 1994, pp. 30–33; (c) L. A. Oro and
D. Carmona, in The Handbook of Homogeneous Hydrogenation,
ed. J. G. de Vries and C. J. Elsevier, Wiley-VCH, Weinheim, 2007,
pp. 14–19; (d) T. Sugimura, T. Uchida, J. Watanabe, T. Kubota,
Y. Okamoto, T. Misaki and T. Okuyama, J. Catal., 2009, 262, 57.
3 (a) H.-U. Blaser, Adv. Synth. Catal., 2002, 344, 17;
(b) S. J. Roseblade and A. Pfaltz, Acc. Chem. Res., 2007, 40,
1402; (c) W. Tang and X. Zhang, Chem. Rev., 2003, 103, 3029.
4 For selected examples of Rh catalysis, see: (a) P. H. Briner, M. C.
T. Fyfe, J. P. Madeley, P. J. Murray, M. J. Procter and F. Spindler,
9 Z. Han, Z. Wang, X. Zhang and K. Ding, Angew. Chem., Int. Ed.,
2009, 48, 5345.
10 Cationic iridium(I) complexes of the SpinPHOX (2) were readily
prepared with a standard procedure reported in ref. 9.
11 For examples of addition of bases, see: (a) K. Yamamoto, K. Ikeda
and L. K. Yin, J. Organomet. Chem., 1989, 370, 319; (b) X. Sun,
L. Zhou, C.-J. Wang and X. Zhang, Angew. Chem., Int. Ed., 2007,
46, 2623; (c) M. E. Fox, M. Jackson, I. C. Lennon, J. Klosin and
K. A. Abboud, J. Org. Chem., 2008, 73, 775.
12 (a) G. Argouarch, O. Samuel and H. B. Kagan, Eur. J. Org. Chem.,
2000, 2885; (b) G. Sarakinos and E. J. Corey, Org. Lett., 1999, 1,
1741; (c) see ref. 7; (d) M. C. T. Fyfe, L. S. Gardner, M. Nawano,
M. J. Procter, C. M. Rasamison, K. L. Schofield, V. K. Shah and
K. Yasuda, Int. Pat., WO 2004/072031, 2004; (e) G. R. Bebernitz
and L. Kirman, Int. Pat., WO 2007/041366, 2007; (f) S. Chen,
P. T. W. Cheng and R. A. Smirk, Int. Pat., WO 2008/005914,
2008.
13 For the impact of molecular chirality on the GK activity, see:
J. Grimsby, R. Sarabu, W. L. Corbett, N.-E. Haynes,
F. T. Bizzarro, J. W. Coffey, K. R. Guertin, D. W. Hilliard,
R. F. Kester, P. E. Mahaney, L. Marcus, L. Qi, C. L. Spence,
J. Tengi, M. A. Magnuson, C. A. Chu, M. T. Dvorozniak,
F. M. Matschinsky and J. F. Grippo, Science, 2003, 301, 370.
ꢀc
This journal is The Royal Society of Chemistry 2010
158 | Chem. Commun., 2010, 46, 156–158